CA1238046A - Dihydropyridyl cyclic imidate esters and their pharmaceutical use - Google Patents

Dihydropyridyl cyclic imidate esters and their pharmaceutical use

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Publication number
CA1238046A
CA1238046A CA000426767A CA426767A CA1238046A CA 1238046 A CA1238046 A CA 1238046A CA 000426767 A CA000426767 A CA 000426767A CA 426767 A CA426767 A CA 426767A CA 1238046 A CA1238046 A CA 1238046A
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Prior art keywords
ethyl
methyl
dihydro
hydro
oxazolyl
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French (fr)
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Davis L. Temple, Jr.
Graham S. Poindexter
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Bristol Myers Co
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Bristol Myers Co
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Abstract

DIHYDROPYRIDYL CYCLIC IMIDATE ESTERS
Abstract of the Disclosure A series of 1,4 dihydropyrid-5-yl cyclic imidate esters have been prepared possessing the general formula wherein R and R1 are independently selected from H, lower alkyl or alkoxyalkyl groups; R2 is lower alkyl, aryl, or hetaryl, R3 is cyclo-alkyl, aryl or hetaryl, generally with electron-withdrawing substituents;
R4 is lower alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, or dialkyl-aminoalkyl; R5 is lower alkyl or aryl; m is 0 or 1; and n is 0, 1, or 2. Compounds of this series demonstrate blockade of calcium ion flux in tissue preparations in vitro and vasodilation in animal testing in vivo.

Field of the Invention The heterocyclic carbon compounds of the present invention are cyclic imidate esters linked directly to the 5- position of substituted 1,4-dihydropyridine moieties and these compounds possess bio-affecting properties.

Description

~38~

Background of the Invention A substantial body of prior art has evolved over the last decade involving compounds of 4-aryl-194-dihydropyridine series which have calcium antagonist properties and are useful in the treatment of cardiovascular diseases. These calcium blocking effects appear to mediate vasodilation which makes these compounds useful in treating angina and hypertension. These structures are typified by nifedipine ( Formul a 1 ); [~
~--N02 H3 C02 C~ Co2 CH3 ,~

3 \N ~ CH3 (1) chemically, 4-(2'-nitrophenyl)-2,6~dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine. Nifedipine and some related 4-aryl-1,4-dihydropyridines are the subject of U.S. Patent No. 3,485,847 issued December 23, 1969.
Numerous subsequent patents have been granted covering 1,4-dihydro-pyridines in which other substituent groups have been employed in the various ring positions of the dihydropyridine moiety. The structure of 15 t~ese later patented compounds which relate to the instant invention can ~e represented by Formula 2.

R 02C~XCO2R

R N
H
(2) r~/ ~
~ 2 ~

3L~3 8~ Ç~

Bossert, et ~1, U.S. 3,48~,359 patented Jan. 6, 1970 and ., ~
3,574,843 pa~ented Apr. 13, 1971 disclose compounds where the variation involves R2 and R4 being alkoxyalkyl groups.
Murakami, et al, Ger. Offen. 2,407,115 disclose compounds where R2 jS a disubstituted aminoalkyl group.
Kojima, et al, U.S. 41220,649 patented September 2, 1980 disclose compounds in which R2 is a pyrrolidine ring.
Loev, et al, U.S. 3,511,847 patented May 12, 1970 list compounds having extensive variation in the nature of R3. Also, the carboxyl groups which bond to R2 and R4 are replaced by carbonyl groups in the disclosure but these compounds are not claimed nor ;s any preparative method given for their synthesis.
Teulon, et al, U.S. 4,096,270 patented June 20, 1978 disclose -: dihydropyridines where R3 is a substituted pyridine moiety.
: ~ 15 In summary, these and other earlier patented dihydropyridine compounds which relate to the instant invention o~n be represented by : Formula 2. In general, Rl, RZ, R4, and R5 are alkyl yroups or alkyl groups bearing miscellaneous substituents, e.g. amine, ether, mercapto groups, etc. The nature of R varies extensively but useful cardio-~0 vascular properties seem maximized when this group is an electron : withdrawing aryl or heterocyclic moiety.
Meyers and Gabel reported in Heterocycles, Vol. 11, pages 133^138 (1978) a new synthesis of 1,4-dihydropyr;dines. This synthes;s utili2es oxazolines as actiYating groups to facilitate organo metallic addition to the pyridine riny to yield 1,4-dihydropyridines ~Formula 3).

~3~

~0~;~ 1~ Ji 0~

(3) No utility was given for these compounds and they were usually converted to pyridines under mild oxidative oondittons.

The present invention includes khe compounds of Formula I
R4~ ~

H3C ~

H R R R

(I) and the acid addition salts of these substances. In the foregoin~
structural formula, the symbols R, Rl, R2, R3, R4, RS, m, and n have the following meaning~. R and Rl are independently s~lec~ed from H, lower alkyl or alkoxyalkyl groups, lower alkyl meaning Cl to C4 and alkoxyalkyl referring to a Cl to C4 alkylene chain and a Cl to C4 alkyl group, connected by an oxy~en atom; R2 jS lower alkyl, phenyl, or thienyl; R3 is cycloalkyl of 5 to 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, hetaryl such as furanyl, indolyl, pyridinyl, thienyl, and the like, aryl meaning phenyl, naphthalenyl, or subs~ituted : 1~ phenyl with the substituents comprising acetamino, Cl-C4 alkyl, C1-C4 alk3xy, cyano~ halogen9 hydroxyl, nitro~ trifluoromethyl 7 ~3J "'~

~ 3~3~ 6 trifluoromethylsulfonyl, and methylsulfonyl and the like; R4 is lower alkyl or alkoxyalkyl as defined above, aminoalkyl, haloalkyl, or dialkylaminoalkyl referring to a Cl to C4 alkylene chain and Cl to C4 alkyl groups connected by a nitrogen atom; R5 is lower alkyl or aryl;
m is 0 or 1; and n is 0, 1, or 2.
The compounds of the present invention can exist as optical isomers and both the racemates of these isomers and the individual racemic modi~ications the~selves are within the scope of the present invention. The racemates an be separated into their individual isomers through well known techniques such as the separation of diastereomeric salts fonmed with optically active acids, followed by conversion back to the optically active bases.
For potential medical use, the pharmaceutically acceptable acid addition salts are preferred. The pharmaceutically acceptable 1~ acid addition salts are those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt~ and as such, they are the pharmacological equivalents of the bases having the foregoing structural formulas. The acid addition salts are obtained either by reaction o~ an organic base of structure I
with an acid~ preferably by contract in solution, or by any of the standard methods detailed in the literature and available to any practitioner s ki 11 ed in the art.
The compounds of this invention were shown to be calcium ian channel blockers on the basis of in vitro pharmacologic testing.
Currently, some calc;um channel blocking agents are being extensively evaluated in patients with coronary heart disease due to the beneficial cardiovascular effects mediated by these agents.

~2~

Biological testing of the subject compounds of For~ula I
using an in vitro smooth muscle tissue preparation demonstrates that -these compounds possess specific blocking action on calcium ion channels.
This in vitro calcium ion channel blocker ~est consists of suspending guinea pig ileal longitudinal smooth musole strips ;n baths containing Tyrodes solution maintained at 37C aerated with 95~ 2 - 5~ C02. The tissues are equilibrated for 6a minutes prior to the start of all experiments. A single response to carbachol is obtained and used in all experiments as a control maximum. In between successive doses, the tissues are re-equilibrated and washed with Tyrodes solution every 15 minutes. To study the effect of the compounds, the tissues are exposed to the antagonist for 10 minutes prior to the additon of carbachol. For all experiments, only one antagonist at any one concentration is tested in any tissue. Results are expressed as molar concentrations of antagonists which inhibit the muscle response by 50,0-Since calciu~ antagonism generally inhibits excitation~
contraction coupling in vascular smooth muscle, agents of this type usually evoke vasodilation. Testing of selected compounds, for example, ethyl 5-(4,4~ [ethyl-5~ 2~zolyl~-6~ethyl-1,4-dihydro 2-methyl-4-~3-nitrophenyl)^3-pyrim,dinecarboxylate and ethyl 5-(4~5-dihydro-2-oxazolyl) 6-ethyl-1,4-dihydro~2~methyl-4-(3-nitrophenyl)-3-pyrimidinecarboxylate; of the instant invention in the ganglion-blocked, angiot2nsin II-supported rat model (Deitchman, et al.9 J.
Pharmacol. Methods, 3, 311-321 (19BO)) demonstrated vasodilation with . . . , _ its concom~itant lowering of blood pressureO
Additionally, these selected compounds of the instant invention have been examined in vitro and in vivo in laboratory tests developed to predict a drug's potential to protect cardiac tissue from injury due to ischemia. These tests utilize the known relationship between ~ 3~3~ 6 progressive depletion of high energy phosphate and the onset of lethal cell injury in ischemic myocardium. Results of these screening tests demonstrate that these selected compounds possess anti-ischemia action.
Pharmaceutical compositions of this invention, in dosage unit form, contain an effective but non-toxic amount of a compound of Formula I and a suitable pharmaceutical carrier. The amount of the Formula I compQund in the composition would range from about 5 ~g to about 500 mg. One skilled in the art will recognize that in deter-mining the amounts of the aotive ingredient in such dosage unit compositions, the activity of the chemical ingredient as well as the size of the host animal must be considered.
Generally, the active ingredients in dosage unit form will be combined with a pharmaceutical carrier. This pharmaceutical carrier may be either a solid or A liquid. Examples of solid carriers would be lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar, pectin, or acacia. Examples of liquid carriers would : be peanut oil, olive oil or sesame oil. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaoeutical forms can be employed. In examples using a solid carrier, the preparation may be tableted, placed in hard gelatin capsules, or put in the form of a lozenge.
The amount of solid carrier will vary widely but generally would be about 25 mg to about 1 9. When a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a liyuid suspension9 or a sterile suspension or solution for parenteral use.
A method of treating via vasodilatation cardiovascular disorders such as ang;na or hypertension, in accordance with this ~23~ 4~

invention comprises adminstering internally to mammals an effective but non-tox;c amount of a compound of Formula I. The active ingredient will preferably be administered in dosage unit form as described above. The route of administration will be oral and/or parenteral.
The compounds of the instant invention are prepared by application of known processes to the appropriate starting ~aterials.
Specifically, the present invention utilizes a process for preparation of the compounds of Formula I according to the following reaction scheme.

R5 lithium R5 R5 O--[CH]m dlisopropyl ~[CH]m o-~CH]m CH3~7~2]n ~ 2~7<CII2~D ~Cl ~n (IV) (II) : 4 R3 o R 2 C~J
R3-CHo ~ CH3CCH2Co2R4 ~ 0 .

(III) ; R5 R4 2 C ~0~ [ CH ] m ~: 3 , 2 R \R
H
(I) ~L~3~6~fL~

In the foregoing scheme, R, Rl, R2, R3, R49 R5, m9 and n are as defined in Formula I. The preferred method for making compounds of Formula I consists of refluxing the intermediate adducts II and III in ethanol solut;on for 18 to 24 hours. Removal of the solvent gives a material which, if it is a solid, is purified by recrystallization and, if it is an oil, is converted to an acid acldition salt and then purified. This facile reaction takes place in ordinary laboratory or plant equipment under convenient operating conditions. Preparation of compounds of Formula I according to the process of the invention generally co~prises heating II and III neat or in the presence of a wide variety of reaction inert organic solvents. Suitable solvents include but are not limited to benzene~ toluene, tetrahydrofuran, dibutylether, butanol, hexanol, methanol, dimethoxyethane, ethylene-glycol~ etc. Suitable reaction temperatures are from about 60 to lS0C. No catalyst or condensation agent is required.
The ;ntermediate cycl;c imidate ester enamines ~ are conveniently prepared by reacting an appropriately substituted metalated methyl heterocycle (IY) with an appropriate nitrile followed by quenching the reaction with ammonium chloride solution.
The intermediate acetylcinnamate compounds of structure III
are prepared utiliz;ng known Knoevenagel condensation reaction conditions.
In general, appropriately substituted aldehydes and acetoacetates were condensed to give III.

Description of_~pecif _ Em odiments The compounds which constitute this invention and ~heir ~ethods of preparation will appear more fully from a consideYation of 3L2 3~3~L~

the fol10wing examples ~nd appended claims which are given for the purpose of illustration only and are not to be construed as limiting the invent;on in sphere or scope. In examples which follow, used to illustrate the foregoing processes9 temperatures are expressed in degrees centrigrade and meltinQ points are uncorrected. The proton nuclear magnetic resonance tNMR~ spectral characteristics refer to chemical shifts (~) expressed as parts per million (ppm) versus tetramethylsilane (TMS) as internal referencP standard. The relative area reported for the various shifts in the proton N~ s~ectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), or doublet ~d).
Abbreviations employed are DM80-d6 (deuterodimethylsulfoxide), CDC13 (deuterochloroform), and are otherwise conventional. The in~rared (IR) spectral descriptions include only absorption wave numbers (cm 1) having functional group identification value. The IR deter-minations were employed using potassium bromide (KBr) as diluent.
The elemental analyses are reported as percent by weight.

SYNTHESIS OF INTERMEDIATES
A. Intermediates_of Formula II

2 _ino-1-~4,5-dihydro-2-oxazolyl)-1-butene A solution of 2-methyl-2-oxa~oline (8.5 9; 0.10 mole) in 100 mL dry tetrahydrofuran (THF) was added via syringe to a stirred 2~ suspension of freshly prepared lithium diisopropylamide in 50 mL THF.
The suspension was kept stirred under a nitrogen atmosphere at -78C
for an additional hour after the addition was completed. At this point propionitrile (10 mL; 0.14 mole~ was added to the stirred suspension which was ~hen allowed to warm to roc,m temperature with continued stirring. The reaction was then quenched with 25 mL
saturated NH~Cl solution. The organic layer was separated and washed with water. The water wash was back extracted with ether and the organic portions combined and washed with brine. The organic solution was dried over K2C03, filtered, and concentrated to 13 9 of yellow liquid. Distillation (90-95C at 1 ~m Hg) yielded 6.5 g clear liquid as product (70% yiPld).

A solution of 2,4,4 triTr~thyl-5-hydr~2-o~a~ol~ne ~25 g;
0.22 mole~ and tetramethylethylenediamine (~5.5 9; 0.~2 mole) w~s added to a stirred mixture of lithium diisopropylamide (freshly prepared from 0.23 mole diis4propylamine and 0.23 mole of n-butyl lithium in 100 mL dry THF) kept under a nitrogen atmosphere at -78C. The resultant whitish suspension was stirred at -78C for an additional 2.5 hr. A solution of acetoni~rile (1~ 9; 0.35 mole) in 50 mL THF was added to the stirred reaction mixture which was then allowed to warm to room temperature. The reaction was then quenched with saturated ammonium chloride solution and water added in a quantity sufficient to dissolve all solids in the mixture. A 100 mL
portion of ether was added and the resulting layers separated. The organic layer was washed with brine and dried (K2C03), filtered~ and concentrated in vacuo to yield 24.9 9 yellow liquid. Distillation afforded a 10~ yield of product enamino oxazoline, b.p. 102-105C at
4 mm Hg.

~;~3~

2-Ami no- 1- ( 5, 6-di hydro4, 4, 6- trimethyl -4H-1 ,3-oxazin-2-yl )-l~butene To a solution of 11.0 mnoles of lithium diisopropylamide (11.1 g diisopropylam;ne; 50 mL of 2.4M n-butyl lithium in n-hexane) in 100 mL THF9 kept at 78C under a nitrogen atmosphere, was added a solu~ion of 5~6-dihydro-4,4~6-trimethyl-4H-1,3-ox~zine (14.1 9; 0.10 mole) in 100 olL THF. The reaction mixture was then allowed to stir at -78 for 2 additional hours at which time a solution of propionitrile (8.3 g; 0.1$ mole) in 50 mL THF was added. ~he reaction mixture was allowed to warm to room temperature and was quenched with 75 mL
saturated NH4Cl solutiQn. A 100 mL portion of ether was added, the organic layer was separated, washed with brine~ and dried (K2C03).
After the K2C03 was removed by filtration; the filtrate was concen-1~ trated in vacuo to gîve 21.2 9 of a yellow liquid which was dis~illed to yield 15.5 9 (79% yield) of product as a pale yellow oil, b.p.
140C at 4 m~ Hg.

2-Amino-1-( 4-metho~ymethyl-4-meth~l-S-hydro-2-oxazolyl~-I-butene . _ _ : ~ A solution of 2,4-c~methyl-4-hydroxymethyl-5-hydro-oxazole [10.0 9; 0.78 mole. For synthesis of this hydroxyoxazoline, ~ cf: H. Witte and ~. Seeliger9 ~2~. Chem., Int. Ed., Vol 11, 287 ; (1972); J. Nys ~nd J. Lib2er~ Bullo SOc~ Chim. Bel~es., Yol. 65, 377 (1956)] in 100 mL THF was added dropwise to a s~irred suspension o~ sodium hydride (3.6 9 of a 57% suspension in mineral oil) in 40 mL dry THF under a nitrogen atmosphere at room temperature. The resulting suspenslon was stirred ~or 3 hr under the nitrogen atmosphere ~3~

and then a solution of methyl iodide (12.1 gj 0.08 mole) in 25 mL
THF was added and the mixture allowed to continue stirr;ng overnight.
A 100 mL portion of ether was added following which th~ layers were separated and the organic layer was washed twice with water and then with brine. The organic layPr was dried (K2C03), filtered, and concentrated ln vacuo to 8.4 9 yellow residual liquor which on dîstillation afforded 4.4 9 (39% y;eld) of clear liquid product9 b.p.
90C at 10 mm Hg.
To a stirred, chilled ( 78C~ mixture of lithium diisopropyl-amide (27 mmoles, prepared from 2.7 g of the amine, 11.3 ml. of 2.4M
n-butyllithium in n-hexane) in 10 mL THF was added a solution of the oxazoline intermediate (3.6 9; 25 mm) prepared above. The resulting yellow mixture was stirred at -78 for 1.5 hr at which time propionitrile (2.8 9; 0.05 mole) in 10 mL THF was added. This mixture was allowed to warm to room temperature and was then quenched with a saturated NH4CI solution. The reaction mixture was then worked up as in the above examples and distillation yielded 1.2 9 (25~ yield) of the product enamino oxazoline, b.p. 120 at 1 mm Hg.
Some additional examples of intermediate~ of Formula II
which can be prepared using the procedure followed in the foregoing examples are given in Table 1.

~3~

Tabl e 1 Additional Formula II Intermediates F~5 RS

O--[CH]m ~[CH]m LiCH2--~ [ cH2]n (IV? (II) Ex. R Rl R2 m R5 n ~ mDC
Me Me Et 0 - 1 70-72 6 Me H Et 0 7 H H Et 0 - 2 8 H H Et 1 Et 9 MeOCH2 Me Me 0 - 2 H Me Ph 0 11 Me Me CHMe2 0 - 1 80 58-61 12 Me Me CMe3 0 - 1 - 132-133 13 Me Me Ph 0 - 1 - 74-75 14 Me Me 2-thienyl 0 - 1 107 69-70 H H Et 1 Ph 1 175(at 2.5m~) -B. Intermediates of Formula III

Ethyl_~-Acetyl-3-nitroc;nnamate :~
A reaction mixture c~ntaining m-nitrobenzaldehyde tl51 9, 1.0 mole), ethyl acetoacetate (130 9, 1.0 mole~, piperidine (4 mL) ; 20 and glacial acetic a~id (12 mL) in 200 mL benzene was reflux~d for 2.5 hr while removing water ~19 mL) by means of a Dean Stark trap.

- 14 - .

~L% 3~ f~

The dark brown reaction solution was allowed to cool to room temperature and was then water washe~ seYeral times and concentrated ln vacuo to give a dark yellow solid. This solid was recrystalli~ed from ethanol to yield 132 9 (69~ yield) of yellow solid, m.p. 103-106C. Literature m.p.: S. Ruhemann, JO Chem. Soc., Vol 83, 717 (1903) --m.p. 110C.
Additional examples of ;ntermediates of Formula III which were prepared using the procedure given in Example 11 are listed ;n Table 2.
Table 2 Additional Formula III Intermediates R3-CHo + CH3CCH2Co2R4 ~
~13C O

(III) Ex R3 R4 (C/O imm) m.p.(~C) 17 m-nitrophenyl i-propyl ~ -15 18 m-ni~rophenyl butyl - -19 m-nitrophenyl methoxyethyl 20 m-nitrophenyl dimethylamino-ethyl 21 ~-nitrophenyl ethyl - 59.5-61.5 22 cyclohexyl ethyl 160-170 23 l-naphthyl ethyl 120-130 24 3-indolyl ethyl - 121-122.5 25 2-furanyl ethyl 118-120 : ?6 2-thienyl ethyl 11~-120 ~L~3~

Table 2 - Continued Ex. R3 R4 (C/O.imm) m.D.(C) 27 3-pyridyl ethyl 145-165 28 2-bicycloheptenyl ethyl 134-140 29 phenyl ethyl 97 30 _-cyanophenyl ethyl 130-160 : 31 o-chlorophenyl ethyl 32 m-hydroxy-p-nitro ethyl - -phenyl 33 o-fluorophenyl ethyl 130 34 m-chlorophenyl ethyl 120-123 35 m-trifluoromethy1- ethyl 100-llQ
phenyl 15 36 p-hydroxy-m-nitro- ethyl - -phenyl 37 _-methoxyphenyl ethyl - -38 m-methylphenyl ethyl 140 : 39 ~-hydroxy-m methoxy- ethyl - 110-112 p-acetomidophenyl . ethyl 41 m-methylsulfonyl- ethyl - -42 m-trifluoromethyl- ethyl sulfonylphenyl -43 o-chloro-m-nitro- ethyl phenyl 44 o-nitrophenyl methyl `~ 45 m-nitrophenyl methyl - 145-146 46 m-nitrophenyl n-propyl 47 m-nitrophenyl 2 chloroethyl - 68-76 ~3~

SYNTHESIS OF PRODUCTS

:~ Ethyl S-( 4t4-dimethyl-5-hydro~2-oxazolyl~-6-eth 1,4-d hydro-2 methy'l-4-~3 ni S A reaction mixture consi5ting of ethy1 a~acetyl-3-nitro-cinnamate (Example 15; 13.2 9, 50.0 mmole), 2-amino-1~( 4,4-dlmethyl-
5-hydro-2-oxazolyl)-l-butene (Exa~ple 5; 8.4 g, 50.0 nmoles) and 75 mL ethanol was refluxed for lg hrs. The mixture was concen~rated in vacuo to 21.0 9 of a yellow solid which was recrystallized from aqueous ethanol to give 17.4 9 (84% yield) yeltow crystals, m.p. 162-163~.
Anal- ~alcd- for C22H27N35 ~ 63.91; H~ 6-59; N~ 10-17-Found: C, 63.90; H, 6.~8; N, 10.13.
This and the other dihydro oxalyl dihydropyridin~ bases of ~he instant inYention are readily convertable to their hydrochloride salts by treating an isopropyl alcohol solution of the base with aqueous HCl foll~wed by eonventional work up and purification.
Conversion of the above base to its monohydrochloride salt gave a yellow solid, m.p. 234-235.
Anal. Cal~d-~or C22H27N305~HCl: C, 58.73j H, 6.27; N, 9.34-Found: C, 58.76, H, 6.43; N, 9.36.
NMR (DMS0-d6): 1.21 (6,t [7.0 Hz]); 1.24 (3,s); 1.51 (3,s);
2.39 ~3.5)i 2.86 ~2,m);:4.08 (2,q 17.n Hz~3; 4.58 (2,s); 5.32 (l,s);
7.59 ~l,t t8.1 Hz]); 7.97 (2,m), 8.28 ~l~m)i 10.64 (l,bs); 12.60 (l,bs).
: 25 IR (KBr): 1065, 1125, 1230, 1270, 1350, 1440~ 1490, 1530, 1585, 1605~ 1700, and ?980 cm 1.

3~

Ethyl 5-(4~5-dihydro-2-oxazolyl)-~ethyl-1,4-dih~dro-2 methyl-4-t3-n_trophenyl)-3-pyridinecarboxylate A mixture of 2-amino-1-(4,5-dihydro-2-oxazolyl)-1-butene (Example 1; 5.0 9, 35.7 mmole) and ethyl a-acetyl-3-nitroclnnamate (Example 15; 9.4`9, 35.7 mmole) in 75 mL ethanol was refluxed 23 hrs.
Concentration of the reaction mixture in vacuo gave 16.6 9 of yellow 501ido Recrystallization from ethanol afforded 11.3 (82% yield~
yellow s~lid, m.p. 149-150C.
Anal. Calcd- for C20H23N35 C, 62-33~ H, 6-02; N~ 10.91.
Found: C, 62.23; H, 5.96; N, 10.75.
Con~ersion of the above base to the hydrochloride salt was accomplished by treating an isopropanol solution of the base with 10,' aqueous HC1. The reaction solution was filtered, conoentrated n vacuo to a yellow solid and recrystallized from methanol to yield yellow solid, m.p. 2Q6-207~C.
NMR (CF3COOH): 1.42 (6,t ~7.4 Hz~); 2.49 (3,s); 3.01 ~2,q 7.4 llz~); 4.11 (27t [9.0 Hz]), 4,3g (2,q [7.4 Hz~); 5.17 (2,t [s.a Hz~);
5.20 (l,s); 7~7~ (2,m); 8.12 (l,bs); 8.21 (l,m), 8.36 (l,m); 8.71 (l,bs).
2ûIR (KBr): 1070, 1130, 1230, 1260, 1285, 1350, 1435, 14909 1530, 1590, 1610, 1700~ and 298Q cm 1.
: EXAMPLE 50 Ethyl 5-[4-(~ethcxymeth~ 4-~ethyl-5-hydrc-2-oxazolyl ~-6-~thyl 1 ,4-dihydro-2-methyl-4-25}~=~ ~
A mixture of 2-amino~l-( 4-methc~ethyl-~-methyl-5-hy~ro-2-oxa~olyl)-1-butene (Example 4; O.g g, 4.6 NmDles) and ethyl a-acetyl-3-nitrocinnamate (Example 15; 1.2 9, ~.0 mnoles~ in 10 mL ethanol was refluxed for 23 hrs. The re~ction mixture was ~3~3~L~

concentrated ln vacuo to a yellQw oil which represented the crude product. This crude base was converted to the hydrochloride salt (isopropyl alcohol and 10,' aqueous HCl) which upon reorystalliza~ion from ethanol yielded 0.25 9 (11.3% yield) yellow solid, m.p. 257-258C
(dec).
Anal. Calcd. for C23H~gN306 HCl: C, 57.56; H, 5.31; N, 8.76.
Found: C, 57.34, H, 6.2~; N 9 8.46.
NMR (DMS0-d6): 1.22 (6,m); 1.44 (3,s); 2.37 (3,s); 2.78 (29m);
2.92 (3,s); 3.27 (2,m); 4.10 (2,q [7.4 Hz~); 4.48 (l,d [8.2 Hz]);
10 4.70 (l,d [8.2 Hz~); 5.31 (l,s); 7.75 (2,m); 8.10 (l~m); 8.28 (l,m);
10.52 (l,bs).
IR (KBr): 1068, 1125, 1225, 1280, 1350, 1440, 1450, 1470, 1495, 1532, 1595, 1620, 1642, and 2~80 cm 1.
:~ EXAMPLE 51 Ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl) -1,4 dihydro-2,6-dimethyl^4-(3-nitro phenyl)-3-pyr inecarboxylate Monohydrochtoride :~ A mixture of 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl) l-propene (Example 2; 2.9 99 18.8 mmoles) and ethyl ~-acetyl-3-20 nitrocinnamate (Example lS; 4.9 9, 18.8 ~moles) in 20 mL ethanol was refluxed for 18 hrs. The reaction mixture was concentrated in vaouo to an orange oil representing the crude product. This crude base was converted to the hydrochloride salt (isopropanol and 10% aqueou~ HCl) to yield 4.25 9 (52~ yield) of yellow crystalline product, m.p. 236C 5dec) after recrystallization ~rom aqueous ethanolO
Ana1- Calcd- for C21H25h'35 HC~ C~ 57-87; H~ 6-02;
N, 9.65. Found: C, 57.71; H, 6.23; N, 9.62.

_ 19 3~

~3~

NMR (DMSO-d~): 1.19 (3~t [6.5 Hz]); 1.24 (3,s~; 1.47 (3,s);
2.36 (3,s); 2.44 (3,s); 4.09 (2,q [6.6 Hz]), 4.53 (2,s); 5.20 (l,s);
7.76 (2,m); 8.09 (l,m); 8.25 (l,m); 10.50 (l,bs).
IR (KBr): 1025, 1125, 1240, 12609 13'iO, 1 M 5, 14859 1530, 1590, 1605, 1700, and 2980 cm 1.

Ethyl 5-(5~6-dihydro-4,4,6~trimethyl-4(H)-1,3-oxazine-2-yl)-6-ethyl-1,4~dihydro-2-methyl-4-(3-nltrophenyl)-~ ~yridineca~ ylate Monohydrochloride A mixture of 2-amino-1-(5,6-dihydro-4,4,6-tr;methyl-4H-1,3^oxazin-2-yl)-1-butene (Example 3; 4.90 9, 25.0 mmole) and ethyl ~-acetyl-3-nitrocinnamate (Example 15; 6.58 9, 25.0 mmole) in 75 mL ethanol was refluxed for 20 hr. Concentration in vacuo yielded a yellow solid which was recrystalliz~d from ethanol to afford 8.9 9 (81% yield) of yellow sol;d9 m.p. 159-163C.
The yellow solid base product prepared above was converted to the hydrochlor;de salt in the same manner as for the previous examples to yield a yellow solid monohydrochloride salt, m.p. 259-260C ~dec).
Anal. Calcd. for C2qH31N305 HCl C, 60.31; H, 6-75;
N, 8.80. Found: C, 60.49; H, 6.78; N, 8.59.
NMR (DMSO-d6): 1.19 (9,m); 1.40 (6,s); 1.90 (2,m);
2.36 ~3,~); 2.60 (2,m); 4.06 (2,q ~7.0 Hz]); 4.83 (l,m); 4.92 (l,s);
7.68 (2,m); 8.09 (2,m); 9.80 (l~bs)O
: : IR (KBr): 1070, 1105, 1125~ 1220, 1265, 13SO, 1485, 1530, 1605, 1620, 1695, and 2975 cm 1.
Additional examples of products of the înstant invention are given in Tab1e 3. These additional products were synthesized using the procedures described in Exam~les 4~-52.

Table 3 3L~3 Additional Formula 1 Products R o?c ~ O ~ CH~

H3C~ ]n Ex. R Rl R R R4 m R5 n 53 H H Et 3-ND2Ph Me O - 1 5 54 Me Me Et 2-furanyl Et O - 1 Me Me Et 4-N02Ph Et O
56 Me Me Et Ph Et O - 1 57 Me Me Et 2-FPh Et O
58 Me Me i-Pr 3-N02Ph Et 0 - 1 ~9 Me Me t-Bu 3-N02Ph Et O - 1 Me Me Ph 3-NO?Ph Et O - 1 61 Me Me 2-thienyl 3-N02Ph Et O - 1 62 Me Me Et 2-Cl-5-N02Ph Et O - 1 - 63 Me Me Et 3-ClPh Et O
~;~ 15 64 Me Me Et 3~CF3Ph Et O
Me Me Et 2-thienyl Et O
66 Me Me Et 4-OH-3-MeOPh Et O
67 Me Me Et 3-MePh Et O
6~ Me Me Et l-naphthalenyl Et o 6g Me Me Et 3-pyridinyl Et 0 - 1 ; 70 Me Me Et 2-ClPh Et O
: i :

.

3 ;~3~

Tabl e 3 - Conti nued Ex. R Rl R2 R3 R4 m R5 n 71 MeMe Et 3-CNPh Et O - 1 72 MeMe Et 2-MeOPh Et O - 1 73 MeMe Et 2-bicycloheptenyl Et O - 1 74 MeMe Et cycl ohexyl Et O
MeMe Et 4-AcNHPh Et O - 1 76 MeMe E~ 3-OH-4-N02Ph Et O - 1 77 Me H Me 4-isobutylphenyl Et 1 Ph 78 HCH20Me Et 4-propoxyphenylEt O
79 MeMe Et 3-ethylphenylMeOCH2CH2 0 MeMe Et 3 CH3S02PhMe2NCH2CH2 0 81 MeCH20Me Et 3-cF3so2Ph Et o 82 MeCH20Me Et 4 CF3S02Ph Me~H2CH2 83 MeMe Et 3-indolyl Et O
84 MeMe Et 4-OH-3-Nû2Ph Et O
H H Et 3- N02Ph i Pr O
86 H l! Et 3-N02Ph MeCH2CH2 87 H H t 3-N02Ph Cl CH2CH2 ~ . 1 88 H H Et 3 N02Ph Et 1 Ph O
89 H H Et 3-N02Ph H2NCH2CH2 0 ;::
.
:

- 2~ -~3~

The physical properties~ where availab'le, of the products of the examples listed in Table 3 are given in Table 4.
Tabl e 4 Physical Properties - Formula I Products .
Anal.
Ex. Name m. p. (C) Cal cd . Found 53 Methyl 5-(4,5-dihydro-2-oxazolyl)- 201~202 C, 55.96 55.99 5-ethyl-1,4~dihydro 2-methyl-4- H, ~.44 5.50 (3-nitrophenyl )-3-pyridine- N9 10.31 10.03 carboxylate monohydrochloride 54 Ethyl 5- (4, 4-dimethyl-5-dihydro - 138.5-140 C, 67.02 66.88 2-oxazolyl)-6-ethyl-4-(2-furanyl)- H, 7.31 7.36 1,4-dihydro-2-methyl-3-pyridine- N, 7.82 7.97 carboxyla~e 15 55 Ethyl 5-( 4,4-dimethyl-5-dihydro - 246-248 C, 58.73 58.36 ; 2-oxazolyl)-6-ethyl-1,4-dihydrc-2- H7 6.?8 6.63 1 methyl-4-(4-nitrophenyl)-3- N, 9.34 9.40 pyridinecarboxylate monohydrochloride 56 Ethyl 5-( 4,4-dimethyl-5-dihydro - 147-149 C, 71.71 71.69 2-oxazolyl)-6-ethyl-1,4-dihydro-2- H, 7.66 7.66 methyl-4-phenyl-3-pyridine- N, 7.60 7.48 carboxylate 57 Ethyl 5-(4,4-dimethyl-5_dihydro - 175-177 C, 62.48 62.41 2-oxa~olyl~-6-ethyl-4-(2-fluoro- H, 6.68 6.70 phenyl)-1,4-dihydro-2 methyl-3- N, 6.63 6.51 pyridinecarboxyl~te monohydrochloride 58 Ethyl 5-(4/4-dimethyl-5_dihydro - 216-217 C, 59.55 59.45 2-oxa;olyl)-1,4-dihydro-2-methyl- H, 6052 5.72 6-(1-methylethyl)-4-~3-nitrophenyl)- N, 9.06 9.41 30 3-pyridinecarboxylate monohydrochloride .
~ 59 Ethyl 5-(4,4-dimethy1-5-dihydro - 155-157 Cl 65.29 64.90 : 2 oxazo1yl~6-(1,1-dimethylethyl)- H,7.08 7.17 1,4-dihydro-2 methyl-4-(3-nitro- N,9.52 9.17 ; pyridinecarboxylate 35 60 Ethyl 5-( 4,4-dimethyl-5-dihydro - 112-113 C,67.67 67.73 2-oxazolyl)-194-dihydro-2-methyl- H,5.90 5.~6 4-(3-nitrophenyl~-6-phenyl-3- N99.11 9.04 pyridinecarboxylate .

_ 23 -Table 4 - Continued 3L~3 8C~ i o Anal cx m.p.( C) Calcd. Found 61 Ethyl 5-( 4,4-dimethyl-5-dlhydr~- 143-145C, 57.20 57.17 S 2-oxazolyl)-1,4-dihydro-2-methyl- H, 5.21 5.31 4-(3-nitrophenyl)-6-(2-thienyl)-3- N, 8.34 8.06 p~yridinecarboxylate monohydroch10ride 62 Ethyl 4-(2-chloro-5-nitrophRny1)- 220-224C, 54.56 54.59 5-(4,4-dimethyl-5-dihydrO-2- H, 5.62 5.70 oxazolyl)-6-ethyl-1,4-dihydro-2- N, 8.68 8.58 methyl-3-pyridinecarboxylate monohydrochloride 63 Ethyl 4-(3-chlorophenyl)-5-(4,4- 170-172.5C~ 65.58 65.62 dimethyl-5-dihydrot2-oxazolyl)- H, 6.75 6.73 6-ethyl-1,4-dihydro-2-methyl-3- N, 6.95 6.84 pyridinecarboxylate C1 8.80 8.83 64 Ethyl 5-( 4,4-dimethyl-5-dihydro- 78-81 C, 63.30 62 95 2-oxazolyl)-6-ethyl-1,4-dihydro-2- H~ 6.24 6 29 methyl-4-[3-(triflueromethyl)phenyl~- N, 6.42 6.12 3-pyridinecarboxylate Ethyl 5-(4,4-dimethyl-5-dihydro- 155-158C, 64.14 63.92 2-oxazolyl ) - 6~ ethyl -1, 4- di hydro- 2- H, 7, 00 7.06 methyl-4-(2-th;enyl )-3-pyridine N, 7.~8 7.17 carboxylate 66 Ethyl 5-( 4,4-dimethyl-5-dihydro- 182-185C, 66.65 66.28 2-oxazolyl)-6-ethyl-1,4-dihydro- H, 7.30 7.32 4-(4-hydroxy-3-methoxyphenyl)-2- N, 6.76 6.54 methyl -3-pyri di necarboxyl ate 67 Ethyl 5-( 4,4-dimethyl-5-dih~dro- 162-163C, 7Z.23 72.01 2-oxa201yl )-6-ethyl-1 ,4-dihydro-2- H,7.91 7.97 methyl~4-~3-methylphenyl~-3- N,7.33 7.25 pyridinecarboxylate 68 Ethyl 5-(4,4-dimethyl 5 dihydr~ 236-238 C,68.~3 68.79 2-oxazolyl )-6-ethyl-1 ,4-dihydro-2- H,6.87 6.65 methy1-4- ( 1-naphthal enyl )-3- N,6.16 5 . 87 pyridinecarboxylate monohydrochloride 69 Ethyl 5-( 4,4-dimethyl-5-dihydro- 161.5-163.5C, 67.94 67.70 2-oxazolyl)-6 ethyl-~l,4-dihydro H, 7.39 t.48 2-~ethyl-4-(3-pyridinyl )-3- N, 11.32 11.22 pyri di necarboxyl a te H20, 0. 49 0 . 5 Ethyl 4-(2-chlorophenyl)-5-(4,4- 179-182 e, 60.15 59.78 dimethyl-5-dihydro-2-oxazolyl~- H~ 6.43 6.18 6-ethyl-1,4-dihydro-2-methyl-3- N, 6.38 6.40 pyridinecarboxylate monohydrochloride Cl, 16.14 16.13 ~ - 24 -:~3~

Table 4 - Continued Anal Ex. Name _ __ m.p. (~C) Calcd. Found 71 thyl 4-~3-cyanophenyl)-5-( 4,4- 179-181 C,70.21 70.15 dLmethyl-5-dihydro-2-oxazolyl~- H,6.92 6.92 6-ethyl-1 ,4-dihydro-2-methyl-3- N,10.68 10.54 pyridinecarboxylate 72 Ethyl 5-( 4~4-dilrethyl-s-dihydro- 230 C963.52 63.22 2-oxazolyl ,~- 6- ethyl -1 9 4- di hydro-4- H,7 D 197 . 20 (2-methoxyphenyl)-2-methyl-3- N,6.45 6.24 pyridineoarboxylate mon~hydrochlor;de Z3 Ethyl 4-(bicyclo[2.2.1lhept-5-en- 165-166.5C, 71.84 72.22 2-yl)-5-( 4,4-dimethyl-5-dihydro, H, 8.39 8.34 2-oxazolyl)-6-ethyl-1,4-dihydro-2- N, 7.29 7.33 methyl-3-pyridirlecar~oxylate 74 Ethyl 4-cyclohexyl-5-(4~4-dimethyl- 205-208C1 64.30 64.14 5-dihydro-2-oxazolyl~-6-ethyl- H, 8~59 8. 56 ~ 1,4-dihydro-2-methyl-3-pyridine- N, 6.82 6.42 :~ carboxylate monohydroohloride ~ `
Ethyl 4-[4-(acetylamino)phenyl]- 240.5-241C, 60.62 60.51 5-(4,4-dimethyl-5-dihydro-2- H, 7.10 7.17 oxazolyl)-6-ethyl-1,4-dihydro-2- N, 8.84 8.51 methyl-3-pyridinecarboxylate H20, 2.84 2.70 monohydrochloride 76 Ethyl 5-~ 4,4-dimethyl-5-dih~dro~ 145.5-146C, 61.53 61.69 2-oxazolyl~-6-ethyl-1,4-dihydro-4- H, 6.34 6.35 (3-hydroxy-4-nitrophenyl)-~- N, 9.79 9.78 ~ methyl-3-pyridinecarboxylate : 83 Ethyl 5-( 4,4-dimethyl 5-dihydro, 124.5-125~, 68.32 68.67 2-oxazolyl~-6-ethyl-1,4-dihydro- H, 7.57 7.45 4-(lH-indol-3-yl)-2-methyl-3- N, 9.56 9.62 pyridinecarboxylate ethanolat~ H20, 2.05 1.97 hemi hydrate 84 Ethyl 5-(4,4-dihydrc~5-dimethu1- 134.5-135C, 56.72 56 62 2-oxazolyl)-6^ethyl-1,4-dihydro- H, 6.06 6.08 :~ 4-(4 hydroxy-3-nitrophenyl)-~- N, 9.02 8.82 methyl-3-pyridineo~rboxylate monohydrochloride :~ 85 l-Methylethyl 5-(415 dihydro-2- 160-161C, 63.17 63.15 oxazo1yl~6-ethyl-1,4-dihydro- H, 6.31 6.38 2-~ethyl-4 (3-nitrophenyl)-3- N, 10.52 10.27 pyridinecarboxylate ~5 -~ 3 8~3l~

Table 4 - Continued Anal.
Ex. Namem.p. (C) Calcd. Found 86 2-methoxyethyl 5-~4,5-dihydro-2- 190-191 C~ 55.8255.65 oxazolyl )-6~ethyl-1 ,4-dihydro-2- H, 5.80 5.77 methyl-4-(3-nitrophenyl)-3- N, 9.30 9.30 pyridinecarboxylate monohydrochloride 88 Ethyl 5-(4 7 5-di hydro-5-phenyl-2- 193-195 C, 62.7262 . 59 oxazolylj-6-ethyl 1,4-dihydro-2- H, 5.67 5.65 methyl-4 (3-nitrophenyl)-3- N, ~.44 8.33 pyridinecarboxylate monohydrochlori de .

Claims (268)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. Process for the manufacture of compounds of formula I

(I) and the acid addition salts thereof, wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is cycloalkyl of 5 to 7 carbon atoms, bicyclo-alkenyl of 7 to 9 carbon atoms,furanyl, indolyl, pyridinyl, thienyl, naphthalenyl, phenyl, or substituted phenyl with the substituents comprising acetamino, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethyl-sulfonyl, and methylsulfonyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkyl-amino-lower alkyl;
R5 is lower alkyl or aryl;
m is 0 or 1; and n is 0, 1, or 2, which comprises heating compounds of formula II

(II) wherein, R, R1, R2, R5, m and n are as defined above, with compounds of formula III

(III) wherein R3 and R4 are as defined above, in the absence or presence of an inert organic solvent, to give compounds of formula I, and/or optionally converting compounds of formula I to their acid addition salts thereof.
2. Process according to claim 1, wherein R2 is lower alkyl, R3 is 3-nitrophenyl, m is 0 and n is 1.
3. Process according to claim 1, wherein R2 is lower alkyl, R3 is 3-nitrophenyl, R4 is lower alkyl, m is 0 and n is 1.
4 Process for the manufacture of compounds of formula I

(I) and the acid addition salts thereof, wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is naphthalenyl, phenyl, or substituted phenyl with the substituents comprising acetamino, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogen, hydroxyl, nitro, tri-fluoromethyl, trifluoromethyl-sulfonyl, and methyl-sulfonyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkyl-amino-lower alkyl:
R5 is lower alkyl or aryl, m is 0 or 1; and n is 0, 1, or 2, which comprises heating compounds of formula II

(II) wherein, R, R1, R2, R5, m and n are as defined above, with compounds of formula III

(III) wherein R3 and R4 are as defined above, in the absence or presence of an inert organic solvent, to give compounds of formula I, and/or optionally converting compounds of formula I to their acid addition salts thereof.

5. Process for the manufacture of compounds of formula I

(I) and the acid addition salts thereof, wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl, R3 is furanyl, indolyl, pyridinyl, thienyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkyl-amino-lower alkyl;
Claim 5 cont'd.

R5 is lower alkyl or aryl:
m is 0 or 1; and n is 0, 1, or 2, which comprises heating compounds of formula II

(II) wherein, R, R1, R2, R5, m and n are as defined above, with compounds of formula III

(III) wherein R3 and R4 are as defined above, in the absence or presence of an inert organic solvent, to give compounds of formula I, and/or optionally converting compounds of formula I to their acid addition salts thereof.
6 A compound having the formula (I) and the acid addition salts thereof wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is cycloalkyl of 5 to 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, furanyl, indolyl, pyridinyl, thienyl, naphthalenyl, phenyl or substituted phenyl with the substituents comprising acetamino, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogen, hydroxyl, nitro , trifluoromethyl, trifluoromethyl-sulfonyl, and methylsulfonyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkylamino-lower alkyl;
R5 is lower alkyl;
m is 0 or 1; and n is 0, 1, or 2.
whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
7. The compound of claim 1 wherein R2 is lower alkyl , R3 is 3-nitrophenyl, m is 0, and n is 1, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
8. A process for the preparation of the compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate which process comprises, refluxing a mixture of ethyl .alpha.-acetyl-3-nitrocinnamate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound, and, if desired, converting said title compound to its hydrochloride salt.
9. A process for the preparation of the compound, ethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate which process comprises, refluxing a mixture of 2-amino-1-(4,5-dihydro-2-oxazolyl)-1-butene and ethyl .alpha.-acetyl-3-nitrocinnamate in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound, and if desired, converting said title compound to its hydrochloride salt.
10. A process for the preparation of the compound ethyl 5-[4-(methoxymethyl)-4-methyl-5-hydro-2-oxazolyl]-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridine-carboxylate which process comprises, refluxing a mixture of 2-amino-1-(4-(methoxymethyl)-4-methyl-5-hydro-2-oxazolyl)-1-butene and ethyl .alpha.-acetyl-3-nitro-cinnamate in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
11. A process for the preparation of the compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate which process comprises, refluxing a mixture of 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-propene and ethyl .alpha.-acetyl-3-nitrocinnamate in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
12. A process for the preparation of the compound, ethyl 5-(5-hydro-4,4,6-trimethyl-4(H)-1,3-oxazine-2-yl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of 2-amino-1-(5-hydro-4,4,6-trimethyl-4H-1,3-oxazin-2-yl)-1-butene and ethyl .alpha.-acetyl-3-nitrocinnamate in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydro-chloride salt.
13. A process for the preparation of the compound methyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate process comprises refluxing a mixture of 2-amino-1-(4,5-dihydro-2-oxazolyl)-1-butene and methyl .alpha.-acetyl-3-nitrocinnamate in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
14. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-4 (2-furanyl)-1,4-dihydro-2-methyl-3-pyridinecarboxylate which process comprises, refluxing a mixture of ethyl 2[(2-furanyl)methylene]3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
15. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1, 4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-[(4-nitrophenyl)methylene]3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydro-chloride salt.
16. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1, 4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-(phenyl-methylene)-3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
17. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-4-(2-fluorophenyl)-1,4-dihydro-2-methyl-3-pyridinecarboxy-late, which process comprises, refluxing a mixture of ethyl 2-[(2-fluorophenyl)methylene]-2-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its mono-hydrochloride salt.
18. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-6-(1-methylethyl)-4-(3-nitrophenyl)-3-pyridine-carboxylate, which process comprises, refluxing a mixture of ethyl .alpha.-acetyl-3-nitrocinnamate and 1-(4,4-dimethyl-5-hydro-2-oxazolyl)-3-methyl-1-buten-2-amine in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
19. A process for the preparation of the compound ethyl 5-( 4,4-dimethyl-5-hydro-2-oxazolyl)-6-(1,1-dimethyl-ethyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate which process comprises, refluxing a mixture of ethyl .alpha.-acetyl-3-nitrocinnamate and 1-( 4,4-dimethyl-5-hydro-2-oxazolyl)-3,3-dimethyl-1-buten-2-amine in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
20. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl .alpha.-acetyl-3-nitrocinnamate and .alpha.-[(4,4-dimethyl-5-hydro-2-oxazolyl)methylene]-benzene methanamine in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
21. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-(2-thienyl)-3-pyridine-carboxylate, which process comprises refluxing a mixture of ethyl 2[(3-nitrophenyl)methylene]-3-oxo-butanoate and .alpha.-[(4,4-dimethyl-5-hydro-2-oxazolyl) methylene]-3-thiophene methanamine in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
22. A process for the preparation of the compound ethyl 4-(2-chloro-5-nitrophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridine-carboxylate, which process comprises, refluxing a mixture of ethyl 2-[(2-chloro-5-nitrophenyl)methylene]-3-oxo-butanoate and 2-amino 1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
23. A process for the preparation of the compound ethyl 4-(3-chlorophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl .alpha.-[(3-chlorophenyl)methylene]-3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydro-chloride salt.
24. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-[3-(trifluoromethyl)phenyl]-3-pyridine-carboxylate, which process comprises, refluxing a mixture of ethyl 2-[(3-trifluoromethyl)phenyl]methylene-3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl) -1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
25. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-thienyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-[(2-thienyl) methylene]-3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
26. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-hydroxy-3-methoxyphenyl)-2-methyl-3-pyridine-carboxylate, which process comprises, refluxing a mixture of ethyl 2[(4-hydroxy-3-methoxyphenyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
27. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-methylphenyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2[(3-methylphenyl)methylene]-3-oxo butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydro-chloride salt.
28. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(1-naphthalenyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-[(1-naphthalenyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
29. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1, 4-dihydro-2-methyl-4-(3-pyridinyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-[(3-pyridinyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
30. A process for the preparation of the compound ethyl 4-(2-chlorophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarbox-ylate, which process comprises, refluxing a mixture of ethyl 2-[(2-chlorophenyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
31. A process for the preparation of the compound ethyl 4-(3-cyanophenyl)-5-(4,4-dimethyl-5-hydro-2 oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarbox-ylate, which process comprises, refluxing a mixture of ethyl 2-[(3-cyanophenyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
32. A process for the preparatlon of the compound ethyl 5-( 4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1, 4-dihydro-4-(2-methoxyphenyl)-2-methyl-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2[(2-methoxyphenyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
33. A process for the preparation of the compound ethyl 4-(bicyclo[2.2.1]hept-5-en-2-yl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-[2-bicycloheptenyl)methylene-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
34. A process for the preparation of the compound ethyl 4-cyclohexyl-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-[(cyclohexyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its mono-hydrochloride salt.
35. A process for the preparation of the compound ethyl 4-[4-(acetylamino)phenyl]-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridine-carboxylate, which process comprises, refluxing a mixture of ethyl 2-[(4-acetamidophenyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its mono-hydrochloride salt.
36. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1, 4-dihydro-4-(3-hydroxy-4-nitrophenyl)-2-methyl-3-pyridinecarboxylate, which process comprises, refluxing a mixture of ethyl 2-[(3-hydroxy-4-nitrophenyl)methylene]-3-oxo-butanoate and 2-amino-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
37. The process of claim 1, wherein R is methyl, R1 is hydrogen, R2 is methyl, R3 is 4-isobutylphenyl, R4 is ethyl, m is 0, R5 is phenyl and n is 1.
38. The process of claim 1, wherein R is hydrogen, R1 is methoxymethyl, R2 is ethyl, R3 is 4-propoxyphenyl, R4 is ethyl, m is 0 and n is 1.
39. The process of claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-ethylphenyl, R4 is methoxyethyl, m is 0 and n is 1.
40. The process of claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-methylsulfonylphenyl, R4 is dimethylaminoethyl, m is 0 and n is 1.
41. The process of claim 1, wherein R is methyl, R1 is methoxymethyl, R2 is ethyl, R3 is trifluoromethyl-sulfonylphenyl, R4 is ethyl, m is 0 and n is 1.
42. The process of claim 1, wherein R is methyl, R1 is methoxymethyl, R2 is ethyl, R3 is 4-trifluoro-methylsulfonylphenyl, R4 is methoxyethyl, m is 0 and n is 1.
43. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1, 4-dihydro-4-(1H-indol-3-yl)-2-methyl-3-pyridinecarboxylate, which process comprises refluxing a mixture of ethyl 2[(3-indolyl)methylene]-3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the 1title compound and, if desired, convert-ing said title compound to its ethanolate hemihydrate form.
44. A process for the preparation of the compound ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1, 4-dihydro-4-(4-hydroxy-3-nitrophenyl)-2-methyl-3-pyridine-carboxylate, which process comprises, refluxing a mixture of ethyl 2-[(4-hydroxy-3-nitrophenyl)methylene]-3-oxo-butanoate and 2-amino-1-(4,4-dimethyl-5-hydro-2-oxazolyl) -1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound to its monohydrochloride salt.
45. A process for the preparation of the compound 1-methylethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of isopropyl 2-[(3-nitrophenyl)methylene]-3-oxo-butanoate and 2-amino-1-(4,5-dihydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its hydrochloride salt.
46. A process for the preparation of the compound 2-methoxyethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of 2-methoxy-ethyl 2-[(3-nitrophenyl)methylene]-3-oxo-butanoate and 2-amino-1-(4,5-dihydro-2-oxazolyl)-1-butene in a suitahle organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
47. A process for the preparation of the compound 2-chloroethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate, which process comprises, refluxing a mixture of 2-chloro-ethyl 2-[(3-nitrophenyl)methylene]-3-oxo-butanoate and 2-amino-1-(4,5-dihydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, convert-ing said title compound to its monohydrochloride salt.
48. A process for the preparation of the compound ethyl 5-(4,5-dihydro-5-phenyl-2-oxazolyl)-6-ethyl-1,4-di-hydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate, which comprises, refluxing a mixture of ethyl .alpha.-acetyl-3-nitrocinnamate and 1-(4,5-dihydro-5-phenyl-2-oxazolyl)-1-buten-2-amine in a sufficient organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
49. A process for the preparation of the compound 2-aminoethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate, which prosess comprises, refluxing 2-aminoethyl 2-[(3-nitrophenyl)methylene]-3-oxo-butanoate and 2-amino-1-(4,5-dihydro-2-oxazolyl)-1-butene in a suitable organic solvent at a suitable temperature for a sufficient time to yield the title compound and, if desired, converting said title compound to its monohydrochloride salt.
50. A process according to claim 1, wherein R
and R1 are both methyl, R2 is ethyl, R3 is 3-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
51. A process according to claim 1, wherein R
and R1 are both hydrogen, R2 is ethyl, R3 is 3-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
52. A process according to claim 1, wherein R
is methoxymethyl, R1 is methyl, R2 is ethyl, R3 is 3-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
53. A process according to claim 1, wherein R, R1 and R2 are each methyl, R3 is 3-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
54. A process according to claim 1, wherein R
and R1 are both methyl, R2 is ethyl, R3 is 3-nitrophenyl, R4 is ethyl, R5 is methyl and m is 0 and n is 1.
55. A process according to claim 1, wherein R
and R1 are both hydrogen, R2 is ethyl, R3 is 3-nitrophenyl, R4 is methyl, m is 0 and n is 1.
56. A process according to claim 1 wherein R and R1 are both methyl, R2 is ethyl, R3 is 2-furanyl, R4 is ethyl, m is 0 and n is 1.
57. A process according to claim 1 wherein R and R1 are both methyl, R2 is ethyl, R3 is 4-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
58. A process accoraing to claim 1 wherein R and R1 are both methyl, R2 is ethyl, R3 is phenyl, R4 is ethyl, m is 0 and n is 1.
59. A process according to claim 1 wherein R and R1 are both methyl, R 2 is ethyl, R3 is 2-fluorophenyl, R4 is ethyl, m is 0 and n is 1.
60. A process according to claim 1, wherein R and R1 are both methyl, R2 is 1-methylethyl, R3 is 3-nitro-phenyl, R4 is ethyl, m is 0 and n is 1.
61. A process according to claim 1 wherein R and R1 are both methyl, R2 is 1,1-dimethylethyl, R3 is 3-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
62. A process according to claim 1, wherein R and R1 are both methyl, R2 is phenyl, R3 is 3-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
63. A process according to claim 1, wherein R and R1 are both methyl, R2 is 2-thienyl, R3 is 3-nitrophenyl R4 is ethyl, m is 0 and n is 1.
64. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 2-chloro-5-nitro-phenyl, R4 is ethyl, m is 0 and n is 1.
65. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-chlorophenyl, R is ethyl, m is 0 and n is 1.
66. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-(trifluoromethyl) phenyl, R4 is ethyl, m is 0 and n is 1.
67. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 2-thienyl, R4 is ethyl, m is 0 and n is 1.
68. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 4-hydroxy-3-methoxy-phenyl, R4 is ethyl, m is 0 and n is 1.
69. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-methylphenyl, R4 is ethyl, m is 0 and n is 1.
70. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 1-naphthalenyl, R4 is ethyl, m is 0 and n is 1.
71. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-pyridinyl, R4 is ethyl, m is 0 and n is 1.
72. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 2-chlorophenyl, R4 is ethyl, m is 0 and n is 1.
73. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-cyanophenyl, R4 is ethyl, m is 0 and n is 1.
74. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 2-bicycloheptenyl, R4 is ethyl, m is 0 and n is 1.
75. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is cyclohexyl, R4 is ethyl, m is 0 and n is 1.
76. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 4-(acetylamino)phenyl, R4 is ethyl, m is 0 and n is 1.
77. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-hydroxy-4-nitro-phenyl, R4 is ethyl, m is 0 and n is 1.
78. A process according to claim 1, wherein R is methyl, R1 is hydrogen, R2 is methyl, R3 is 4-isobutyl-phenyl, R4 is ethyl, m is 1, R5 is phenyl and n is 1.
79. A process according to claim 1, wherein R is hydrogen, R1 is methoxymethyl, R2 is ethyl, R3 is 4-propoxyphenyl, R4 is ethyl, m is 0 and n is 1.
80. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-ethylphenyl, R4 is methoxyethyl, m is 0 and n is 1.
81. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-methylsulfonylphenyl, R4 is dimethylaminoethyl, m is 0 and n is 1.
82. A process according to claim 1, wherein R is methyl, R1 is methoxymethyl, R2 is ethyl, R3 is 3-trifluoro-methylsulfonylphenyl, R4 is ethyl, m is 0 and n is 1.
83. A process according to claim 1, wherein R is methyl, R1 is methoxymethyl, R2 is ethyl, R3 is 4-trifluoro-methylsulfonylphenyl, R4 is methoxyethyl, m is 0 and n is 1.
84. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 3-indolyl, R4 is methyl, m is 0 and n is 1.
85. A process according to claim 1, wherein R and R1 are both methyl, R2 is ethyl, R3 is 4-hydroxy-3-nitrophenyl, R4 is ethyl, m is 0 and n is 1.
86. A process according to claim 1, wherein R and R1 are both hydrogen, R2 is ethyl, R3 is 3-nitrophenyl, R4 is 1-methylethyl, m is 0 and n is 1.
87. A process according to claim 1, wherein R and R1 are both hydrogen, R2 is ethyl, R3 is 3-nitrophenyl, R4 is methoxyethyl, m is 0 and n is 1.
88. A process according to claim 1, wherein R and R1 are both hydrogen, R2 is ethyl, R3 is 3-nitrophenyl, R4 is chloroethyl, m is 0 and n is 1.
89. A process according to claim 1, wherein R and R1 are both hydrogen, R2 is ethyl, R3 is 3-nitrophenyl, R4 is ethyl, m is 1, R5 is phenyl and n is 0.
90. A process according to claim 1, wherein R and R1 are both hydrogen, R2 is ethyl, R3 is 3-nitrophenyl, R4 is aminoethyl, m is 0 and n is 1.
91. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
92. The compound, ethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridine-carboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
93. The compound, ethyl 5-[4-(methoxymethyl)-4-methyl-5-hydro-2-oxazolyl]-6-ethyl-1,4-dihydro-2-methyl--4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
94. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
95. The compound, ethyl 5-(5-hydro-4,4,6-trimethyl-4(H)-1,3-oxazine-2-yl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
96. The compound, methyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridine-carboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.
97. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-4-(2-furanyl)-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
98. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.
99. The compound, ethyl 5-(4,4-dimethyl-5-hydro--2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.
100. The compound, ethyl 5-(4,4-dimethyl-5-hydro--2-oxazolyl)-6-ethyl-4-(2-fluorophenyl)-1,4-di-hydro-2-methyl-3-pyridinecarboxylate or the hydrochloride chloride salt thereof, whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
101. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-6-(1-methylethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.
102. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-(1,1-dimethylethyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 19 or hy an obvious chemical equivalent thereof.
103. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.
104. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-(2-thienyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.
105. The compound, ethyl 4-(2-chloro-5-nitrophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2 methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.
106. The compound, ethyl 4-(3-chlorophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.
107. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-[3-(trifluoro-methyl)phenyl]-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.
103. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-thienyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.
109. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-hydroxy-3-methoxyphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 26 or by an obvious chemical equivalent thereof.
113. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-methylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.
111. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(1-naphthalenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 28 or by an obvious chemical equivalent thereof.
112. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-pyridinyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 29 or by an obvious chemical equivalent thereof.
113. The compound, ethyl 4-(2-chlorophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 30 or by an obvious chemical equivalent thereof.
114. The compound, ethy1 4 (3-cyanophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 31 or by an obvious chemical equivalent thereof.
115. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(2-methoxyphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 32 or by an obvious chemical equivalent thereof.
116. The compound, ethyl 4-(bicyclo[2.2.1]-5-en-2-yl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 33 or by an obvious chemical equivalent thereof.
117. The compound, ethyl 4-cyclohexyl-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 34 or by an obvious chemical equivalent thereof.
118. The compound, ethyl 4-[4-(acetylamino)phenyl]-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-2-methyl-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 35 or by an obvious chemical equivalent thereof.
119. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-hydroxy-4-nitrophenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 36 or by an obvious chemical equivalent thereof.
120. The compound of claim 6, ethyl 5-(4,5-dihydro-4-methyl-5-phenyl-2-oxazolyl)-6 methyl-1,4-dihydro-4-(4-isobutylphenyl)-2-methyl-3 pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 37 or by an obvious chemical equivalent thereof.
121. The compound of claim 6, ethyl 5-(4,5-dihydro-4-methoxymethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-propoxyphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 38 or by an obvious chemical equivalent thereof.
122. The compound of claim 6, methoxyethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-ethylphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 39 or by an obvious chemical equivalent thereof.
123. The compound of claim 6, dimethylaminoethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-methylsulfonylphenyl)-2-methyl-3-pyridine-carboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 40 or by an obvious chemical equivalent thereof.
124. The compound of claim 6, ethyl 5-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-trifluoromethylsulfonylphenyl)-2-methyl-3-pyridine-carboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 41 or by an obvious chemical equivalent thereof.
125. The compound of claim 6, methoxyethyl 5-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-4-(4-trifluoromethylsulfonylphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 42 or by an obvious chemical equivalent thereof.
126. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(1H-indolyl-3-yl)-2-methyl-3-pyridinecarboxylate or its ethanolate hemi-hydrate form thereof, whenever prepared by the process of claim 43 or by an obvious chemical equivalent thereof.
127. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-hydroxy-3-nitrophenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 44 or by an obvious chemical equivalent thereof.
128. The compound,1-methylethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 45 or by an obvious chemical equivalent thereof.
129. The compound, 2-methoxyethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 46 or by an obvious chemical equivalent thereof.
130. The compound, 2-chloroethyl 5-(4,5 dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 47 or by an obvious chemical equivalent thereof.
131. The compound ethyl 5-(4,5-dihydro-5-phenyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 48 or by an obvious chemical equivalent thereof.
132. The compound, 2-aminoethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 49 or by an obvious chemical equivalent thereof.
133. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of chloride 50 or by an obvious chemical equivalent thereof.
134. The compound of claim 6, ethyl 5-(4,5-di-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 51 or by an obvious chemical equivalent thereof.
135. The compound of claim 6, ethyl 5-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 52 or by an obvious chemical equivalent thereof.
136. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazoly)-1,4-dihydro-2,6-di-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 53 or by an obvious chemical equivalent thereof.
137. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-4,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 54 or by an obvious chemical equivalent thereof.
138. The compound of claim 6, methyl 5-(4,5-di-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 55 or by an obvious chemical equivalent thereof.
139. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-furanyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 56 or by an obvious chemical equivalent thereof.
140. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 57 or by an obvious chemical equivalent thereof.
141. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 58 or by an obvious chemical equivalent thereof.
142. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-fluorophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 59 or by an obvious chemical equivalent thereof.
143. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-(1-methylethyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process or claim 60 or by an obvious chemical equivalent thereof.
144. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-(1,1-dimethylethyl)-1,4-dihydro-2-methyl-4-(3 nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 61 or by an obvious chemical equivalent thereof.
145. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-(oxazolyl)-6-phenyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 62 or by an obvious chemical equivalent thereof.
146. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-(2-thienyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 63 or by an obvious chemical equivalent thereof.
147. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-chloro-5-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 64 or by an obvious chemical equivalent thereof.
148. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-chlorophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 65 or by an obvious chemical equivalent thereof.
149. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-(trifluoromethyl)phenyl)-3-pyridinecarboxylate, or the hydrochloride salt thereof, whenever prepared by the process of claim 66 or by an obvious chemical equivalent thereof.
150. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-thienyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 67 or by an obvious chemical equivalent thereof.
151. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-hydroxy-3-methoxyphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof whenever prepared by the process of claim 68 or by an obvious chemical equivalent thereof.
152. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-methylphenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 69 or by an obvious chemical equivalent thereof.
153. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl 1,4-dihydro-2-methyl-4-(1-naphthalenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 70 or by an obvious chemical equivalent thereof.
154. The compound of claim 6, ethyl 5-(4,4-di-methyl)-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-pyridinyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 71 or by an obvious chemical equivalent thereof.
155. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(2-chlorophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 72 or by an obvious chemical equivalent thereof.
156. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-cyanophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 73 or by an obvious chemical equivalent thereof.
157. The compound of claim 6, ethyl 4-(bicyclo-[2.2.1]hept-5-en-2-yl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridine-carboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 74 or by an obvious chemical equivalent thereof.
158. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-cyclohexyl-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 75 or by an obvious chemical equivalent thereof.
159. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-(acetylamino)phenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 76 or by an obvious chemical equivalent thereof.
160. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-hydroxy-4-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 77 or by an obvious chemical equivalent thereof.
161. The compound of claim 6l ethyl 5-(5,6-di-hydro-4-methyl-6-phenyl-1,3 oxazin-2-yl)-1,4-dihydro-2,6-dimethyl-4-(4-isobutylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 78 or by an obvious chemical equivalent thereof.
162. The compound of claim 6, ethyl 5-(4-methoxy-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2 methyl-4-(4-propoxyphenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 79 or by an obvious chemical equivalent thereof.
163. The compound of claim 6, methoxyethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-ethylphenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof, whenever prepared by the process of claim 80 or by an obvious chemical equivalent thereof.
164. The compound of claim 6, dimethylaminoethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-2-methyl-4-(3-methylsulfonylphenyl)-3-pyridine-carboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 81 or by an obvious chemical equivalent thereof.
165. The compound of claim 6, ethyl 5-(4-methyl-4-methoxymethyl)-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-trifluoromethylsulfonylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 82 or by an obvious chemical equivalent thereof.
166. The compound of claim 6.methoxyethyl-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-trifluoromethylsulfonylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 83 or by an obvious chemical equivalent thereof.
167. The compound of claim 6, methyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-indolyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 84 or by an obvious chemical equivalent thereof.
168. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-hydroxy-3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 85 or by an obvious chemical equivalent thereof.
169. The compound of claim 6, 1-methylethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 86 or by an obvious chemical equivalent thereof.
170. The compound of claim 6, methoxyethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 87 or by an obvious chemical equivalent thereof.
171. The compound of clalm 6, chloroethyl 5-(4,5-di-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitro-phenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 88 or by an obvious chemical equivalent thereof.
172. The compound of claim 6, ethyl 5-(4,5-di-hydro-5-phenyl-2-oxazolyl)-6-ethyl-1,4-clihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 89 or by an obvious chemical equlvalent thereof.
173. The compound of claim 6, aminoethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl 4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 90 or by an obvious chemical equivalent thereof.
174. A process according to claim 1, characterized in that a compound of the formula I according to claim 1, is manufactured,wherein R, R1 and R5 are each methyl, R2 is ethyl, R3 is 3-nitrophenyl, R4 is ethyl, and m and n are both 1.
175. A compound according to claim 6, ethyl 5-(5,6-dihydro-4,4,6-trimethyl-4H-1,3-oxazin-2-yl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof, whenever prepared by the process of claim 174 or by an obvious chemical equivalent thereof.
176. A process as in claim 5 wherein hetaryl is furanyl.
177. A process as in claim 5 wherein aryl is phenyl.
178. A compound having the formula (I) and the acid addition salts thereof wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is naphthalenyl, phenyl, or substituted phenyl with the substituents comprising acetamino, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogen, hydroxyl, nitro, tri-fluoromethyl, trifluoromethyl-sulfonyl and methyl-sulfonyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkylamino-lower alkyl;
R5 is lower alkyl or aryl;
m is 0 or 1; and n is 0, 1, or 2 whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.
179. A compound having the formula (I) and the acid addition salts thereof wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is furanyl, indolyl, pyridinyl, thienyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkylamino-lower alkyl;

R5 is lower alkyl or aryl;
m is 0 or 1; and n is 0, 1 or 2, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
180. A compound having the formula (I) and the acid addition salts thereof wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is cycloalkyl of 5 to 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, furanyl, indolyl, pyridinyl, thienyl, naphthalenyl, phenyl or substituted phenyl with the substituents com-prising acetamino, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, and methylsulfonyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkylamino-lower alkyl;
R5 is lower alkyl;
m is 0 or 1; and n is 0, 1, or 2.
181. The compound of claim 180 wherein R2 is lower alkyl, R3 is 3-nitrophenyl, m is 0, and n is 1.
182. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
183. The compound, ethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridine-carboxylate or the hydrochloride salt thereof.
184. The compound, ethyl 5-[4-(methoxymethyl)-4-methyl-5-hydro-2-oxazolyl]-6-ethyl-1,4-dihydro-2-methyl--4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
185. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
186. The compound, ethyl 5-(5-hydro-4,4,6-trimethyl-4(H)-1,3-oxazine-2-yl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
187. The compound, methyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridine-carboxylate or the hydrochloride salt thereof.
188. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-4-(2-furanyl)-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
189. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
190. The compound, ethyl ?-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
191. The compound, ethyl 5-(4,4-dimethyl-5-hydro--2-oxazolyl)-6-ethyl 4-(2-fluorophenyl)-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
192. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-6-(1-methylethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
193. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6- (1,1-dimethylethyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
194. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
195. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl) 6-(2-thienyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
196. The compound, ethyl 4-(2-chloro-5-nitrophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
197. The compound, ethyl 4-(3-chlorophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
198. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-[3-(trifluoro-methyl)phenyl]-3-pyridinecarboxylate or the hydrochloride salt thereof.
199. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-thienyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
200. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-hydroxy-3-methoxyphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
201. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-methylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
202. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(1-naphthalenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
203. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl 4-(3-pyridinyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
204. The compound, ethyl 4-(2-chlorophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
205. The compound, ethyl 4-(3-cyanophenyl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
206. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(2-methoxyphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
207. The compound, ethyl 4-(bicyclo[2.2.1]-5-en-2-yl)-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
208. The compound, ethyl 4-cyclohexyl-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
209. The compound, ethyl 4-[4-(acetylamino)phenyl]-5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
210. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-hydroxy-4-nitrophenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
211. The compound of claim 6, ethyl 5-(4,5-dihydro-4-methyl-5-phenyl-2-oxazolyl)-6-methyl-1,4-dihydro-4(4-isobutylphenyl)-3-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
212. The compound of claim 6, ethyl 5-(4,5-dihydro-4-methoxymethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-propoxyphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
213. The compound of claim 6, methoxyethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-ethylphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
214. The compound of claim 6, dimethylaminoethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-methylsulfonylphenyl)-2-methyl-3-pyridine-carboxylate or the hydrochloride salt thereof.
215. The compound of claim 6, ethyl 5-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(3-trifluoromethylsulfonylphenyl)-2-methyl-3-pyridine-carboxylate or the hydrochloride salt thereof.
216. The compound of claim 6, methoxyethyl 5-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-4-(4-trifluoromethylsulfonylphenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
217. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(1H-indolyl-3-yl)-2-methyl-3-pyridinecarboxylate or its ethanolate hemi-hydrate form thereof.
218. The compound, ethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-hydroxy-3-nitrophenyl)-2-methyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
219. The compound, 1-methylethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
220. The compound, 2-methoxyethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
221. The compound, 2-chloroethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
222. The compound, ethyl 5-(4,5-dihydro-5-phenyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
223. The compound, 2-aminoethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
224. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
225. The compound of claim 6, ethyl 5-(4,5-di-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
226. The compound of claim 6, ethyl 5-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
227. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-1,4-dihydro-2,6-di-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
228. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-4,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
229. The compound of claim 6, methyl 5-(4,5-di-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
230. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-furanyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
231. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
232. The compound of claim 6, ethyl 5-(4,4 di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate or the hydrochloride salt thereof.
233. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-fluorophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
234. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-(1-methylethyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
235. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-(1,1-dimethylethyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
236. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro 2-(oxazolyl)-6-phenyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
237. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-(2-thienyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
238. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-chloro-5-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
239. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-chlorophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
240. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-(trifluoromethyl)phenyl)-3-pyridinecarboxylate, or the hydrochloride salt thereof.
241. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(2-thienyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
242. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-hydroxy-3-methoxyphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
243. The compound of claim 6, ethyl 5-(4,4-di methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-methylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
244. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(1-naphthalenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
245. The compound of claim 6, ethyl 5-(4,4-di-methyl)-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-pyridinyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
246. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(2-chlorophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
247. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-cyanophenyl)-3 pyridinecarboxylate or the hydro-chloride salt thereof.
248. The compound of claim 6, ethyl 4-(bicyclo-[2.2.1]hept-5-en-2-yl)-5-(4,4 dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-3-pyridine-carboxylate or the hydrochloride salt thereof.
249. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-cyclohexyl-3-pyridinecarboxylate or the hydro-chloride salt thereof.
250. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-(acetylamino)phenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
251. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-hydroxy-4-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
252. The compound of claim 6, ethyl 5-(5,6-di-hydro-4-methyl-6-phenyl-1,3-oxazin-2-yl)-1,4-dihydro-2,6-dimethyl-4-(4-isobutylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
253. The compound of claim 6, ethyl 5-(4-methoxy-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-propoxyphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
254. The compound of claim 6, methoxyethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-ethylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
255. The compound of claim 6, dimethylaminoethyl 5-(4,4-dimethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-di-hydro-2-methyl-4-(3-methylsulfonylphenyl)-3-pyridine-carboxylate or the hydrochloride salt thereof.
256. The compound of claim 6, ethyl 5-(4-methyl-4-methoxymethyl)-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-trifluoromethylsulfonylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
257. The compound of claim 6, methoxyethyl-(4-methyl-4-methoxymethyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-trifluoromethylsulfonylphenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
253 The compound of claim 6, methyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-indolyl)-3-pyridinecarboxylate or the hydro-chloride salt thereof.
259. The compound of claim 6, ethyl 5-(4,4-di-methyl-5-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-hydroxy-3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
260. The compound of claim 6, 1-methylethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
261. The compound of claim 6, methoxyethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
262. The compound of claim 6, chloroethyl 5-(4,5-di-hydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitro-phenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
263. The compound of claim 6, ethyl 5-(4,5-di-hydro-5-phenyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
264. The compound of claim 6, aminoethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
265. A compound according to claim 6, ethyl 5-(5,6-dihydro-4,4,6-trimethyl-4H-1,3-oxazin-2-yl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate or the hydrochloride salt thereof.
266. A compound having the formula (I) and the acid addition salts thereof wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is naphthalenyl, phenyl, or substituted phenyl with the substituents comprising acetamino, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogen, hydroxyl, nitro, tri-fluoromethyl, trifluoromethyl-sulfonyl and methyl-sulfonyl;

R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkylamino-lower alkyl;
R5 is lower alkyl or aryl;
m is 0 or 1; and n is 0, 1, or 2
267. A compound having the formula (I) and the acid addition salts thereof wherein R and R1 are independently selected from H, lower (C1-C4) alkyl or lower alkoxy-lower alkyl groups;
R2 is lower alkyl, phenyl, or thienyl;
R3 is furanyl, indolyl, pyridinyl, thienyl;
R4 is lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, halo-lower alkyl, or di-lower alkylamino-lower alkyl;
R5 is lower alkyl or aryl;
m is 0 or 1; and n is 0, 1, or 2.
268. A therapeutic composition for treating cardiovascular disorders by vasodilatation comprising a compound according to claim 180, 181 or 182, together with a pharmaceutically acceptable carrier.
CA000426767A 1982-03-22 1983-04-26 Dihydropyridyl cyclic imidate esters and their pharmaceutical use Expired CA1238046A (en)

Applications Claiming Priority (5)

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US06/360,758 US4414213A (en) 1982-03-22 1982-03-22 Dihydropyridyl cyclic imidate esters and their pharmaceutical use
LU84797A LU84797A1 (en) 1982-03-22 1983-05-10 CYCLIC DIHYDROPYRIDYLIMIDATES
BE0/210755A BE896727A (en) 1982-03-22 1983-05-11 CYCLIC DIHYDROPYRIDYLIMIDATES.
AU81943/87A AU606630B2 (en) 1982-03-22 1987-11-30 Acetylcinnamate compounds
AU81942/87A AU608260B2 (en) 1982-03-22 1987-11-30 Cyclic imidate ester enamine compounds

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JP (1) JPS59204189A (en)
AT (1) AT377259B (en)
AU (3) AU566346B2 (en)
BE (1) BE896727A (en)
CA (1) CA1238046A (en)
CH (1) CH654837A5 (en)
DE (1) DE3317691A1 (en)
FR (1) FR2545826B1 (en)
GB (1) GB2139212B (en)
LU (1) LU84797A1 (en)
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SE (3) SE457725B (en)

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BE896727A (en) 1983-11-14
SE457725B (en) 1989-01-23
FR2545826A1 (en) 1984-11-16
SE8404458L (en) 1984-10-26
LU84797A1 (en) 1984-03-07
SE8302332D0 (en) 1983-04-25
JPS59204189A (en) 1984-11-19
AU1426083A (en) 1984-11-08
AU608260B2 (en) 1991-03-28
SE8404458D0 (en) 1984-09-05
AU606630B2 (en) 1991-02-14
DE3317691A1 (en) 1984-11-22
AU8194387A (en) 1988-04-14
SE8302332L (en) 1984-10-26
SE8404459D0 (en) 1984-09-05
JPH0545595B2 (en) 1993-07-09
SE8404459L (en) 1984-10-26
AU566346B2 (en) 1987-10-15
CH654837A5 (en) 1986-03-14
GB2139212B (en) 1987-12-09
AT377259B (en) 1985-02-25
NL8301672A (en) 1984-12-03
ATA181483A (en) 1984-07-15
GB8311433D0 (en) 1983-06-02
US4414213A (en) 1983-11-08
SE460194B (en) 1989-09-18
AU8194287A (en) 1988-04-14
FR2545826B1 (en) 1985-08-23
GB2139212A (en) 1984-11-07

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